Perfluorooctane sulfonate induces apoptosis of cerebellar granule cells via a ROS-dependent protein kinase C signaling pathway

Lee, Hyun-Gyo; Lee, Youn Ju; Yang, Jae‐Ho

doi:10.1016/j.neuro.2012.01.017

Cited by 82 publications

(28 citation statements)

References 33 publications

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“…A classical study at the single cell level has demonstrated that execution phase of apoptosis ensues mainly due to depletion of GSH [43]. Induction of oxidative stress has been shown to activate caspase-3 and 7 resulting in enhancing sensitivity to apoptosis in neurons [44,45]. Thus, the observed prevention of ETOH-induced caspase 3/7 activity in Nrf2 depleted neurons could be attributed to abundant supply of GSH from astrocytes that are likely to limit ROS-mediated caspase 3/7 activation.…”

Section: Resultsmentioning

confidence: 99%

Astrocytes Prevent Ethanol Induced Apoptosis of Nrf2 Depleted Neurons by Maintaining GSH Homeostasis

Narasimhan

Rathinam

Patel

et al. 2012

OJApo

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Glutathione (GSH), a major cellular antioxidant protects cells against oxidative stress injury. Nuclear factor erythroid 2-related factor 2 (NFE2L2/Nrf2) is a redox sensitive master regulator of battery of antioxidant enzymes including those involved in GSH antioxidant machinery. Earlier we reported that ethanol (ETOH) elicits apoptotic death of primary cortical neurons (PCNs) which in partly due to depletion of intracellular GSH levels. Further a recent report from our laboratory illustrated that ETOH exacerbated the dysregulation of GSH and caspase mediated cell death of cortical neurons that are compromised in Nrf2 machinery (Narasimhan et al., 2011). In various experimental models of neurodegeneration, neuronal antioxidant defenses mainly GSH has been shown to be supported by astrocytes. We therefore sought to determine whether astrocytes can render protection to neurons against ETOH toxicity, particularly when the function of Nrf2 is compromised in neurons. The experimental model consisted of co-culturing primary cortical astrocytes (PCA) with Nrf2 downregulated PCNs that were exposed with 4 mg/mL ETOH for 24 h. Monochlorobimane (MCB) staining followed by FACS analysis showed that astrocytes blocked ETOH induced GSH decrement in Nrf2-silenced neurons as opposed to exaggerated GSH depletion in Nrf2 downregulated PCNs alone. Similarly, the heightened activation of caspase 3/7 observed in Nrf2-compromised neurons was attenuated when co-cultured with astrocytes as measured by luminescence based caspase Glo assay. Furthermore, annexin-V-FITC staining followed by FACS analysis revealed that Nrf2 depleted neurons showed resistance to ETOH induced neuronal apoptosis when co-cultured with astrocytes. Thus, the current study identifies ETOH induced dysregulation of GSH and associated apoptotic events observed in Nrf2-depleted neurons can be blocked by astrocytes. Further our results suggest that this neuroprotective effect of astrocyte despite dysfunctional Nrf2 system in neurons could be compensated by astrocytic GSH supply.

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Section: Resultsmentioning

confidence: 99%

Astrocytes Prevent Ethanol Induced Apoptosis of Nrf2 Depleted Neurons by Maintaining GSH Homeostasis

Narasimhan

Rathinam

Patel

et al. 2012

OJApo

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“…The complicated processes taking place during development make the brain and neural tissue sensitive to a variety of environmental contaminants [15,16]. Previous studies have demonstrated the ability of POPs such as perfluorooctanesulfonic acid (PFOS) to pass through the blood−brain barrier [17], causing neurotoxicity and behavioural alterations in mice, rats, and zebrafish [18,19,20,21,22,23]. As for the potential mechanisms, work in zebrafish has demonstrated that POPs such as PFOS can promote cell death in the brain following early life exposure which is then associated with altered behaviour [20].…”

Section: Introductionmentioning

confidence: 99%

A Mixture of Persistent Organic Pollutants and Perfluorooctanesulfonic Acid Induces Similar Behavioural Responses, but Different Gene Expression Profiles in Zebrafish Larvae

Khezri

Fraser

Nourizadeh-Lillabadi

et al. 2017

IJMS

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Persistent organic pollutants (POPs) are widespread in the environment and some may be neurotoxic. As we are exposed to complex mixtures of POPs, we aimed to investigate how a POP mixture based on Scandinavian human blood data affects behaviour and neurodevelopment during early life in zebrafish. Embryos/larvae were exposed to a series of sub-lethal doses and behaviour was examined at 96 h post fertilization (hpf). In order to determine the sensitivity window to the POP mixture, exposure models of 6 to 48 and 48 to 96 hpf were used. The expression of genes related to neurological development was also assessed. Results indicate that the POP mixture increases the swimming speed of larval zebrafish following exposure between 48 to 96 hpf. This behavioural effect was associated with the perfluorinated compounds, and more specifically with perfluorooctanesulfonic acid (PFOS). The expression of genes related to the stress response, GABAergic, dopaminergic, histaminergic, serotoninergic, cholinergic systems and neuronal maintenance, were altered. However, there was little overlap in those genes that were significantly altered by the POP mixture and PFOS. Our findings show that the POP mixture and PFOS can have a similar effect on behaviour, yet alter the expression of genes relevant to neurological development differently.

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“…While cytoxicity was observerd in Vero cells [55], neonatal gonocyte and Sertoli cells [56], ESCs-derived cardiomyocytes [57], Neural stem cells [58], Cerebellar granule cells [59], human adrenocortical carcinoma [60] after PFOS exposure (<100 µM), the morphology and AP staining of mESCs were unchanged up to 200 μΜ of PFOS. However, as we mentioned above, the expression level of Nanog was decreased at 0.2 µM and the expression level of Sox2 was decreased at 2 µM.…”

Section: Discussionmentioning

confidence: 99%

Perfluorooctane Sulfonate Disturbs Nanog Expression through miR-490-3p in Mouse Embryonic Stem Cells

Chen

Mao

et al. 2013

PLoS ONE

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Perfluorooctane sulfonate (PFOS) poses potential risks to reproduction and development. Mouse embryonic stem cells (mESCs) are ideal models for developmental toxicity testing of environmental contaminants in vitro. However, the mechanism by which PFOS affects early embryonic development is still unclear. In this study, mESCs were exposed to PFOS for 24 h, and then general cytotoxicity and pluripotency were evaluated. MTT assay showed that neither PFOS (0.2 µM, 2 µM, 20 µM, and 200 µM) nor control medium (0.1% DMSO) treatments affected cell viability. Furthermore, there were no significant differences in cell cycle and apoptosis between the PFOS treatment and control groups. However, we found that the mRNA and protein levels of pluripotency markers (Sox2, Nanog) in mESCs were significantly decreased following exposure to PFOS for 24 h, while there were no significant changes in the mRNA and protein levels of Oct4. Accordingly, the expression levels of miR-145 and miR-490-3p, which can regulate Sox2 and Nanog expressions were significantly increased. Chrm2, the host gene of miR-490-3p, was positively associated with miR-490-3p expression after PFOS exposure. Dual luciferase reporter assay suggests that miR-490-3p directly targets Nanog. These results suggest that PFOS can disturb the expression of pluripotency factors in mESCs, while miR-145 and miR-490-3p play key roles in modulating this effect.

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Perfluorooctane sulfonate induces apoptosis of cerebellar granule cells via a ROS-dependent protein kinase C signaling pathway

Cited by 82 publications

References 33 publications

Astrocytes Prevent Ethanol Induced Apoptosis of Nrf2 Depleted Neurons by Maintaining GSH Homeostasis

Astrocytes Prevent Ethanol Induced Apoptosis of Nrf2 Depleted Neurons by Maintaining GSH Homeostasis

A Mixture of Persistent Organic Pollutants and Perfluorooctanesulfonic Acid Induces Similar Behavioural Responses, but Different Gene Expression Profiles in Zebrafish Larvae

Perfluorooctane Sulfonate Disturbs Nanog Expression through miR-490-3p in Mouse Embryonic Stem Cells

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